title: Wnt/beta-catenin signaling is an essential and direct driver of myelin gene expression and myelinogenesis.
abstract: Wnt/β-catenin signaling plays a major role in the development of the nervous system and contributes to neuronal plasticity. However, its role in myelination remains unclear. Here, we identify the Wnt/β-catenin pathway as an essential driver of myelin gene expression. The selective inhibition of Wnt components by small interfering RNA or dominant-negative forms blocks the expression of myelin protein zero (MPZ) and peripheral myelin protein 22 (PMP22) in mouse Schwann cells and proteolipid protein in mouse oligodendrocytes. Moreover, the activation of Wnt signaling by recombinant Wnt1 ligand increases by threefold the transcription of myelin genes and enhances the binding of β-catenin to T-cell factor/lymphoid-enhancer factor transcription factors present in the vicinity of the MPZ and PMP22 promoters. Most important, loss-of-function analyses in zebrafish embryos show, in vivo, a key role for Wnt/β-catenin signaling in the expression of myelin genes and in myelin sheath compaction, both in the peripheral and central nervous systems. Inhibition of Wnt/β-catenin signaling resulted in hypomyelination, without affecting Schwann cell and oligodendrocyte generation or axonal integrity. The present findings attribute to Wnt/β-catenin pathway components an essential role in myelin gene expression and myelinogenesis.
authors.affiliation: Unité Mixte de Recherche 788, Inserm and University Paris-Sud 11, Biomedical Institute of Bicêtre, 94276 Kremlin-Bicêtre, France.
authors.forename: Marcel
authors.initials: M
authors.lastname: Tawk
authors.forename: Joelle
authors.initials: J
authors.lastname: Makoukji
authors.forename: Martin
authors.initials: M
authors.lastname: Belle
authors.forename: Cosima
authors.initials: C
authors.lastname: Fonte
authors.forename: Amalia
authors.initials: A
authors.lastname: Trousson
authors.forename: Thomas
authors.initials: T
authors.lastname: Hawkins
authors.forename: Huiliang
authors.initials: H
authors.lastname: Li
authors.forename: Said
authors.initials: S
authors.lastname: Ghandour
authors.forename: Michael
authors.initials: M
authors.lastname: Schumacher
authors.forename: Charbel
authors.initials: C
authors.lastname: Massaad
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D015870:Gene Expression; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D018993:Myelin P0 Protein / Q000235:genetics / Q000378:metabolism; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism; D009186:Myelin Sheath / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D018993:Myelin P0 Protein; D009185:Myelin Proteins; C489545:Pmp22 protein, mouse; D051153:Wnt Proteins; D051176:beta Catenin